Successful Targeted Treatment of a Medically Actionable Mutation in Psychotic Disorders

Background: The identification of mutations in specific genes could enable personalized, “medically actionable” treatment interventions. We identified a potentially informative mutation, a rare structural rearrangement that includes a triplication of the glycine decarboxylase gene (GLDC). GLDC is the enzyme that catabolizes glycine, a co-agonist of the NMDA receptor (NMDAR). Four copies of GLDC would be expected to accelerate the degradation of glycine, resulting in low levels of brain glycine and NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of psychotic disorders. Carriers of this mutation may especially benefit from augmentation of psychotropic drug treatment with glycine or other NMDAR co-agonist site modulators. Methods: We carried out a double-blind placebo-controlled clinical trial (six weeks per arm), followed by six weeks of open-label glycine, in two related individuals who are carriers of the GLDC mutation, one with a diagnosis of bipolar disorder with psychotic features and the other with a diagnosis of schizo-affective disorder. Clinical assessments were carried out every two weeks using the PANSS, BPRS, YMRS, HAM-D, and CGI. Results: Here, we report that the subjects showed dramatic clinical improvements while on glycine both during blinded and open label glycine treatment. Both subjects relapsed when glycine augmentation was discontinued. Subsequent resumption of glycine augmentation restored the symptom remission observed previously. Conclusion: Other carriers of duplications or triplications of GLDC, or carriers of other genetic variants resulting in NMDAR hypofunction, also may benefit from augmentation with glycine or other NMDAR positive modulators, regardless of clinical phenotype.